The present invention relates to methods for the treatment of disease states which result from neoplastic cell proliferation. In another aspect, the present invention relates to compounds and compositions which are useful for carrying out the above-referenced methods.
Neoplastic cell proliferation is the underlying cause of a wide variety of diseases, e.g., breast cancer, leukemia, colon cancer, prostate cancer, and the like. Traditional approaches to treatment of neoplastic cell proliferation include surgery, chemotherapy, radiotherapy, and the like, as well as combinations thereof. Unfortunately, conventional methods for the treatment of neoplastic cell proliferation require major invasive procedures, induce a variety of undesirable side effects, and/or lead to complete response in only a small percentage of cases. Thus, for many patients, conventional methods of treatment are largely palliative.
Thus, for example, with respect to Liposarcoma, which is the most common soft tissue malignancy in adults, accounting for at least 20% of all sarcomas in this age group, localized disease is treated primarily with surgery, often in combination with radiotherapy. Metastatic liposarcoma is associated with an extremely poor prognosis, with average five year survival ranging from 70% to 25%, depending on the type of tumor. Unfortunately, conventional chemotherapy for metastatic liposarcoma leads to complete response in only about 10% of cases. Thus, for most liposarcoma patients, conventional chemotherapy is largely palliative.
Induction of terminal differentiation represents a promising alternative to conventional methods of treatment for certain malignancies. For example, the retinoic acid receptor alpha (RARxcex1), which plays an important role in the differentiation and malignant transformation of cells of myelocytic lineage, has been used as a target for intervention in acute promyelocytic leukemia. Indeed, differentiation therapy with all-trans retinoic acid has become the standard of care for this disease. In view of this success, it has been speculated that nuclear receptors that regulate growth and differentiation of other cell types may also represent potential targets for differentiation therapy.
Accordingly, the development of effective, non-invasive methods for treating a variety of disease states which result from neoplastic cell proliferation would represent a significant advancement in the therapeutic arts.
In accordance with the present invention, we have discovered that PPARxcex3 is expressed consistently in tissues associated with each of a variety of disease states which result from neoplastic cell proliferation. It has further been discovered that maximal activation of PPARxcex3 with exogenous ligand promotes terminal differentiation of primary cells which are otherwise subject to neoplastic cell proliferation. Thus, cells undergoing neoplastic cell proliferation can be induced to differentiate, thereby blocking further proliferation thereof.
In accordance with the present invention, it has still further been discovered that RXR-specific ligands are also potent agents for induction of differentiation of cells expressing the PPARxcex3/RXRxcex1 heterodimer, and that simultaneous treatment of cells subject to neoplastic cell proliferation with a PPARxcex3-selective ligand, in combination with an RXR-specific ligand, results in an additive stimulation of differentiation. Accordingly, according to the invention, there have been identified compounds and compositions which are useful for the treatment of a variety of disease states which result from neoplastic cell proliferation.